Aims: To investigate the factors affecting the quality of life among adults with comorbid serious mental illness and chronic diseases. Design: Descriptive, cross‐sectional study design. Methods: In total, 204 patients with serious mental illness were recruited from two hospitals. Self‐reported data were collected using the Brief Psychiatric Rating Scale, Internalised Stigma of Mental Illness, Patient Activation Measure and brief version of the World Health Organization Quality of Life Instrument. Data were collected between July 2018 – January 2019. The structural equation model was applied to examine the associations among the study variables. Results: Internalized stigma (β = −0.479, p =.002) had the greatest direct effect on quality of life, followed by patient activation (β = 0.238, p =.002), severity of comorbidities (β = −0.207, p =.002) and psychiatric symptoms (β = −0.186, p =.006). In addition, psychiatric symptoms directly influenced the severity of comorbidities, which in turn directly influenced internalized stigma and then in turn directly influenced patient activation and ultimately influenced quality of life. Conclusion: The relationship between internalized stigma and quality of life is significantly mediated by patient activation. This finding provides a theoretical basis for developing patient activation interventions for patients with comorbid mental and chronic diseases, which potentially improve the quality of life of this population. Impact: Multiple comorbidities cause impaired quality of life in patients with serious mental illnesses. We found that patient activation plays an important role in the management of chronic diseases for achieving more favourable quality of life, but this is negatively affected by internalized stigma. These findings can help mental health professionals develop tailored intervention strategies to enhance quality of life by promoting patient activation and reducing internalized stigma, psychiatric symptoms, and comorbidity severity in patients with comorbid serious mental illnesses and chronic diseases. [ABSTRACT FROM AUTHOR]